1. Field of the Invention
The invention relates to a novel process for the preparation of 2-alkyl-3,5,6,7 or 8 -substituted-4(3H)-quinazolinones. This process has the advantages of providing a high yield of a purer product in a more efficient and less costly way.
2. Description of the Prior Art
The compounds prepared by the process of the present invention, namely the 2-alkyl-3,5,6,7 or 8 -substituted-4(3H)-quinazolinone compounds of the following formula: ##STR2## where R, R.sup.1 and R.sup.2 are defined hereinafter are important intermediates useful in the preparation of therapeutic 2,3,6-substituted quinazolinones which are useful as angiotensin II receptor blocking agents. The 2,3,6,7, or 8-substituted quinazolinone compounds and uses for such compounds are described in the following published European patent applications, EP-253310, EP-324377 and EP-497150.
The methods described in these prior art references for the preparation of these substituted-4(3H)- quinazolinones require high temperatures which generally give rise to appreciable quantities of undesired by-products resulting in low and variable yields of product.
As described in EP-497150, the usual method to prepare the 2,3,6,7 or 8-substituted-4(3H)-quinazolinones involves reaction of the appropriately substituted aminobenzoic acid with valeric anhydride which under high vacuum is heated to give a 3,1,4-benzoxazolinone. Upon concentration, the benzoxazolinone is then treated with ammonium hydroxide-ethyl alcohol to give the desired quinazolinone. Such methods, although useful for laboratory preparations, are less suitable for commercial scale manufacturing processes.
It has now been found that 2-alkyl-3,5,6,7 or 8-substituted-4(3H)-quinazolinone compounds may be advantageously synthesized in large scale from N-aroyl or N-acyl substituted anthranilic acids. Reaction with ethylchloroformate followed by further reaction with ammonia or a primary amine gives the desired products which are formed in higher yield and purity and with reaction workups which are less labor and time intensive than the prior art.